Discovery of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II.
Discovery of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II.
复制标题
发现高效和选择性α4β2-烟碱乙酰胆碱受体(nAChR) 部分激动剂，含有异恶唑基吡啶醚支架，具有抗抑郁样活性。
DOI：
10.1021/jm301177j
复制
发表时间：
2012
影响因子：
7.3
通讯作者：
Kozikowski,AlanP
中科院分区：
文献类型：
--
作者：
Yu,Li-Fang;Eaton,JBrek;Fedolak,Allison;Zhang,Han-Kun;Hanania,Taleen;Brunner,Dani;Lukas,RonaldJ;Kozikowski,AlanP
在我们持续努力开发具有独特作用机制的新型抗抑郁药α4β2-烟碱乙酰胆碱受体（nAChR）部分激动剂的过程中，对某些异恶唑基吡啶醚类化合物的构效关系（SAR）进行了探索。特别是，对起始结构4中存在的氮杂环丁烷环及其代谢上易受影响的羟基侧链取代基的修饰已被探索以改善化合物的可药用性。所有新化合物的药理学特性已经进行了使用[3 H]epibatidine结合研究与功能测定的基础上on 86 Rb+离子通量测量。我们发现，代谢上易受影响的羟基基团的缺失或其被氟甲基基团取代不仅保持了效力和选择性，而且还导致化合物在小鼠强迫游泳试验中显示出抗抑郁剂样性质。这些isoxazolylpyridine醚似乎代表有前途的领先候选人在设计创新的化学工具，含有报告基团的成像目的和可能的治疗。
In our continued efforts to develop α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure–activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure4and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [3H]epibatidine binding studies together with functional assays based on86Rb+ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.